Thrombosis is a serious threat to human life and health,and can easily lead to death and disability.In recent decades,researchers have been trying to find the ideal"antithrombotic-anticoagulant-thrombectomy"drugs.Thrombin,as an important component in the coagulation cascade,is also associated with the corresponding physiological functions of platelets.It is regarded as an effective target and has been the focus of research for several generations.Based on this,related inhibitors have been successfully launched,and until today,many drugs are still in clinical use.This article will mainly introduce the three major varieties of thrombin inhibitors that have been launched,namely dabigatran etexilate,argatroban,Bivalirudin.
Dabigatran etexilate
Aβ-alanine non-peptide direct thrombin inhibitor with a molecular mass of 628,a prodrug,which is converted into dabigatran with antithrombin activity in the liver after oral or gastrointestinal absorption.It was developed by Boehringer Ingelheim in Germany,and its trade name is Pradaxa.
Oral dabigatran etexilate has a dose-related anticoagulant effect between 5 and 30 mg/kg,and also has a time-dependent effect.The plasma concentration reaches a peak at 0.5 to 2 hours after oral administration,and the plasma concentration reaches 3 days after repeated administration.Steady state,the half-life is 12 to 14 hours,and the half-life increases with age.The main excretion route of dabigatran etexilate is renal excretion.Some residual drugs combine with glucuronic acid to form acetyl glucuronic acid and are excreted by bile,so patients with renal insufficiency should reduce the dosage.
Attached table:Clinical situation of dabigatran etexilate in China in recent years
In terms of the market,the global sales of dabigatran etexilate in the past five years have all been between US$1 billion and US$2 billion,which is a blockbuster drug.The overall market is relatively stable,as shown in the figure below.
Domestic registration application:In 2011,the products of the original research company Boehringer Ingelheim were approved for import;in 2013,domestic pharmaceutical companies Nanjing Huawei,Qilu Anti,Lianyungang Hongchuang,Jiangsu Haosen,Qilu Pharmaceutical,Tianjin Hanrui,Sichuan Haisco,Chongqing Medical and Industrial Institute,Chia Tai Tianqing,Shandong Luoxin,Sichuan Qingmu,Chengdu Xinheng,Chongqing Shenghuaxi,Chengdu Yuandong,Guilin Nanyao,Shaanxi Buchang,Guizhou Yibai,Jiangxi Sinopharm,Chenxin Pharmaceutical,They have successively applied for imitation;but as of now,there is no domestic wholesale enterprise.
Argatroban
Chemically synthesized low-molecular-weight arginine derivative,with a relative molecular weight of 527,the structural formula contains a triangular structure composed of arginine-piperidine-quinoline,which binds to the active center of thrombin in a non-covalent and reversible manner,crystal structure The study showed that the hydrophobic part of argatroban interacts with the hydrophobic pocket adjacent to the active site of thrombin.
(Argatroban&Thrombin~Crystal Information)
Argatroban is administered by intravenous injection.The initial dose is 2μg/(kg/min),and the steady-state plasma concentration is reached in 10 hours.About 54%of argatroban is bound to plasma proteins in the blood,and the half-life is about 39～51min,not affected by age,gender and renal function.Argatroban is metabolized in the liver and excreted in bile and feces.There is no need to reduce the dose in the case of renal insufficiency,but the monitoring should be strengthened and the dose should be appropriately reduced in the case of hepatic insufficiency.
Attached table:Clinical situation of argatroban in China in recent years
In the market,due to the limitations of indications and use methods,this variety has not grown into a blockbuster disease drug;the global sales peak appeared in 2011,with sales of less than 240 million US dollars,and the sales in the past five years were all<1.In the field of cardiovascular drugs,especially in the field of antithrombotics and anticoagulation,it is not a"big variety".
Domestic registration application,except for the argatroban variety of Tianjin Pharmaceutical Research Institute,which was approved for production more than ten years ago,dozens of pharmaceutical companies have registered and applied for registration(most of them are registered in the old 6 categories),but so far Not approved for production;these companies include many well-known domestic pharmaceutical companies,such as Chia Tai Tianqing,Yangzijiang Pharmaceutical,Shandong Luoxin,CSPC,etc.
Bivalirudin
Synthetic eicoseptide,developed by Medi-cines,with a relative molecular weight of 2180,was approved by the FDA as early as December 15,2000 for patients undergoing percutaneous coronary angioplasty.The binding of bivalirudin to thrombin is reversible,and the peptide bond between Arg3-Pro4 is easily broken by thrombin after binding,so that the catalytic activity of thrombin is quickly restored,so its half-life is only 20-25min.Bivalirudin is mainly eliminated after being degraded by peptidase,and part of it is excreted in the original form by the kidneys.
Bivalirudin is considered to have many advantages:strong specificity,specific direct inhibition of thrombin activity,and inhibition of thrombin-bound thrombin;short half-life,reversible thrombin inhibition,coagulation effect can be predicted;Degraded by endogenous polypeptide enzymes,it can be safely used in patients with renal impairment,and patients with mild renal impairment do not need to adjust the treatment plan,and anticoagulation and antithrombotics are safe and effective.However,there are also many defects,such as narrow therapeutic window,significant increase in severe bleeding,and due to the particularity of the polypeptide structure,it can only be administered intravenously,which causes many inconveniences in clinical application.
Attached table:Clinical situation of bivalirudin in China in recent years
Market situation:Since its launch,bivalirudin has not grown into a blockbuster drug in the field of antithrombotics and anticoagulation.The sales of the original research company's products in 2014 were US$636 million(peak),while in the past three years Sales have fallen sharply,to just$6.1 million in 2018.
Registration and application of this variety in China:In 2006,the Chinese People's Liberation Army General Hospital,Chengdu Shengnuo,Beijing Youbo Pharmaceutical,Shanghai Soho Yiming,Xi'an Xintong Pharmaceutical,Shenzhen Wanle Pharmaceutical,Hainan Zhonghe Pharmaceutical,Jiangsu Hansoh Pharmaceutical,Changzhou Siyao Pharmaceutical,Shenzhen Xinlitai,Hangzhou Tiger,Shenyang Yaoda Pharmaceutical,and Fanbiao Pharmaceutical have successively registered and applied;among them,Shenzhen Xinlitai(2011)and Jiangsu Hanson(2014)were awarded the batch production.
Summary
Although,in the field of antithrombotic-anticoagulation,the market of thrombin inhibitors is not as good as clopidogrel and ticagrelor,which are P2Y12 receptor antagonists,nor as well as the hot Xa inhibitors rivaroxaban and apixaban in recent years.But it is undeniable that the status of thrombin in the whole field of antithrombotic-anticoagulation is still worthy of attention.It can also be seen from the registration distribution of domestic pharmaceutical companies that the target and its inhibitors are by no means a niche.But what needs to be evaluated objectively is that,based on the physiological function position of the target and the performance of drug development over the years,although the dabigatran etexilate,argatroban and bivalirudin we see today are well known to us,but the subsequent development of better drugs for this target is not easy.
[ Source:Yaozhi.com ]
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